3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide is known to be useful as therapeutic agent for treating many pathological conditions, including the treatment or prevention of inflammatory and respiratory diseases. The efficacy of 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide is believed to be related to its ability to inhibit p38 kinase.
It is believed that p38α kinase can cause or contribute to the effects of, for example, inflammation generally; arthritis; neuroinflammation; pain; fever; pulmonary disorders; cardiovascular diseases; cardiomyopathy; stroke; ischemia; reperfusion injury; renal reperfusion injury; brain edema; neurotrauma and brain trauma; neurodegenerative disorders; central nervous system disorders; liver disease and nephritis; gastrointestinal conditions; ulcerative diseases; ophthalmic diseases; opthalmological conditions; glaucoma; acute injury to the eye tissue and ocular traumas; diabetes; diabetic nephropathy; skin-related conditions; viral and bacterial infections; myalgias due to infection; influenza; endotoxic shock; toxic shock syndrome; autoimmune disease; bone resorption diseases; multiple sclerosis; disorders of the female reproductive system; pathological (but non-malignant) conditions, such as hemaginomas, angiofibroma of the nasopharynx, and avascular necrosis of bone; benign and malignant tumors/neoplasia including cancer; leukemia; lymphoma; systemic lupus erthrematosis (SLE); angiogenesis including neoplasia; and metastasis.
WO03/068,230A1, published on Aug. 21, 2003, describes 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide, its preparation and use in the treatment of inflammation.
3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide and closely related analogs can be made by either the following described racemic route (Route 1) or chiral route (Route 2).
In efforts to make the discovery route more efficient and a scalable process, several modifications have been introduced in Route 1. These not only include improved reaction conditions and workup procedures but also new reactions. The sequence of steps 2, 3, and 4 of the discovery route-alkylation, hydrolysis and bromination- was changed to bromination, alkylation and hydrolysis for a variety of reasons. These include avoiding tedious workup at each step, such as multiple extractions and concentrations and to obtain higher yields. Route 1 avoids the use of costly materials where possible.
Route 2 was initiated to develop a novel chiral route towards the preparation of a compound of Formula I to eliminate the need for chiral chromatography. An efficient and scalable chiral synthesis was identified by utilizing a selective enzymatic hydrolysis approach. Route 2 also avoids the use of costly materials where possible.